P887: IN-HOUSE ANTI BCMA CAR-T THERAPY FOR THE TREATMENT OF RELAPSED REFRACTORY MULTIPLE MYELOMA: PHASE 1 RESULTS.
Authors: N. Asherie, S. Kfir-Erenfeld, B. Avni, S. Grisariu, M. Assayag, T. Sharon, E. Lebel, C. J. Cohen, M. E. Gatt, P. Stepensky
Journal: HemaSphere (2022)

Background: B-Cell Maturation Antigen (BCMA) targeted CAR-T cell therapy is a treatment strategy showing great promise. Recently, anti-BCMA CAR-T cell therapy has been approved by the FDA for treatment of relapsed/refractory multiple myeloma. However, the major drawbacks of this treatment are the length of the manufacturing process, limited access and the excessive cost. Thus, there is an urgent need for development of in-house manufactured CAR-T cell treatments. Based on favorable pre-clinical results using our novel CAR-T-anti BCMA construct, in February 2021 we have launched a BCMA-targeted CAR-T cell based clinical trial treating relapsed refractory (R/R) multipe myeloma (MM) patients (NCT04720313). Aims: This phase I-II clinical trial is a dose escalation study. The first goal was to explore the safety of our product. The phase I first part of the trial consisted of three escalating cell doses ranging between 150- and 800x10^6 CAR+ cells. Methods: We enrolled 20 R/R MM patients having failed more than three lines of previous therapies, to receive our CAR-T-anti BCMA product at escalating doses of 150 x 106 (cohort 1, 6 patients), 450 x 106 (cohort 2, 7 patients) and 800 x 106 (cohort 3, 7 patients) cells. The median age was 62 (range: 44-75) years, with a median time of 55 months from initial disease diagnosis (range, 8-241) and a median number of 5.5 previous treatment lines (range, 3-13). Eighty percent had bone marrow (BM) involvement and the majority were categorized as ISS/R-ISS II. The vast majority of patients underwent previous autologous BM transplantation and were refractory to proteasome inhibitors, immunomodulatory agents (IMiD) and anti-CD38 antibody, while only 10 patients (50%) were previously exposed to an anti-BCMA agent (belantamab). Patients in cohort 1 had a higher rate of extramedullary disease, high LDH and massive BM involvement (>50% plasma cells in BM biopsy), while patients in cohort 3 had a higher ECOG performance score and a lower rate of cytogenetic high-risk disease. Results: At a median follow up of 156 days, overall response was 75% for the entire cohort with 2/6,1/7 and 1/7 patients not responding in cohorts 1, 2 and 3, respectively. Six patients achieved MRD negative CR (4 of them in cohort 3), while 3 achieved MRD positive (or MRD not evaluated) CR and 6 had achieved VGPR (4 of them in cohort 2). The median PFS for the entire study group was 166 days (range, 24-289); 75 days (range, 24-289), 181 days (range, 61-209) and not reached (range, 20-124) for cohort 1,2 and 3, respectively. The median duration of response (DOR) for the entire study group was 151 days (range, 32-259). The progression rate in patients exposed to belantamab, was higher (7/9, 78%) compared to the non-exposed patients (4/11, 36%). On the day of last follow up, 75% of patients were still alive. Eleven (55%) patients progressed. Four (25%) patients died due to disease progression. Ninety percent of patients developed cytokine release syndrome (CRS), mostly on the day of cell infusion (median day 0, range 0-21), while none suffered from grade 3-4 CRS. None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANS). Summary/Conclusion: The anti-BCMA CART - cell therapy developed at Hadassah Medical Center proves safe at the three cohorts, with manageable toxicities and evidence of initial short term favorable responses attesting to its efficacy in heavily pretreated R/R MM patients. These data are very encouraging and demonstrate the capability of single center local medical institution to develop, manufacture and deliver in-house CART.